Abstract (from the parent grant) This research proposal aims at improving interstitial photodynamic therapy (I-PDT) for patients with locally advanced head and neck cancer (LAHNC). Currently there is no effective treatment for these patients. In I- PDT, systemic administration of a light sensitive drug (photosensitizer, PS) is followed by intratumoral illumination with diffusing fiber(s). We have recently treated five patients with LAHNC using I-PDT and porfimer sodium (Photofrin), the FDA approved PS. These patients were treated off label and in a pilot clinical study. In these settings we used our treatment planning and integrated dosimetry system, with approval from the local IRB and FDA, to provide a proof of principle of our technology in a peer reviewed publication. Our system worked as anticipated. However, tumor response was disappointing and inconsistent with our expectations based on our large experience with external beam (EB) illumination in the PDT of head and neck cancer. Our computer simulations and preliminary animal studies suggest that the historical laser setting for diffusing fibers will result in a very high intratumoral fluence rate, which were known to adversely affect the efficacy of PDT with Photofrin. Thus, we are convinced that this high fluence rate is not optimal. We stipulate that optimal intratumoral fluence rate is essential for an effective I-PDT with Photofrin. In this proposal, we will employ the power of our novel integrated treatment planning and dosimetry system to define, for the first time, the optimal intratumoral fluence rate and fluence for Photofrin mediated I-PDT. We hypothesize that our integrated treatment planning and dosimetry system, with optimal light fluence rate and fluence, will improve the response to I-PDT of LAHNC. To test this hypothesis, we propose to pursue a stepwise approach with the following aims: Aim 1. Define optimal fluence rate and fluence for Photofrin I-PDT with our light dosimetry system in preclinical models. We will define the optimal fluence rate and fluence in an animal model with simple tumor geometry, and test the optimal fluence rate and fluence in another preclinical model of more complex geometry and anatomical location. Aim 2. Establish the optimal fluence rate for Photofrin I-PDT in patients with LAHNC. The objective of this aim is to test the optimal fluence rate in patients with LAHNC. Hence, in completing the proposed aims, we will significantly advance the potential benefit of I-PDT for patients with LAHNC, who have no effective therapy. Our ultimate goal is to maximize the therapeutic benefits of I-PDT for patients with LAHNC. The wider impact of the current proposal is in validating a system that has the potential to improve the administration of I-PDT for locally advanced cancer in other anatomical sites.